Stimulating the Production of Utrophin Protects
Muscular Dystrophy Mice from Muscle Wasting

(Philadelphia, PA) - Researchers at the University of Pennsylvania
School of Medicine report a novel strategy for stimulating the
production of utrophin - an important muscle protein in young mice - for
muscular dystrophy therapy. The investigators gave mdx mice (the mouse
model for Duchenne's muscular dystrophy) heregulin, a small molecule to
turn on the production of utrophin in their muscles. Utrophin improved
muscle function in the mdx mice. “Our strategy boosts the levels
of an existing gene using pre-existing cellular machinery rather than
having to deliver a gene via gene therapy,” says lead author Tejvir
S. Khurana, MD, PhD, Assistant Professor of Physiology &
Member of the Pennsylvania Muscle Institute.

They detected an approximately threefold increase of utrophin levels over
control mdx mice. “This is the level at which one starts seeing
a therapeutic affect, as measured in lab tests with mouse muscles,”
says Khurana. The researchers noted an improvement in the quality of mouse
muscle tissue, the biomechanical properties of muscles, and biochemical
indices of dystrophy in the muscles.

In
patients with Duchenne's muscular dystrophy (DMD), the gene to make the
protein dystrophin is missing, which results in the muscle wasting that
is associated with the disease. (Click on thumbnail above to view full-size
image). The progressive muscle wasting begins in early childhood and typically
leads to death in the twenties. “The gene for utrophin is already
in the body, so by giving a small peptide to stimulate its production,
we’re bypassing the need for dystrophin by cranking up the levels
of utrophin,” explains Khurana. This research appears in the September
21 issue of the Proceedings of the National Academy of Sciences.

Utrophin (also called dystrophin-related protein) is found on chromosome
6 and functions much the same as dystrophin, which is found on the X chromosome.
However, utrophin is made in large amounts in fetal muscles, after which
dystrophin takes over throughout adult life as one of the main muscle-membrane-associated
proteins. “This approach reawakens the body to make utrophin again,”
says Khurana. “And it doesn’t preclude possible gene-therapy
treatments for muscular dystrophy. Utrophin enrichment is a parallel strategy
with great potential of being used in combination with other approaches.”

Despite these advances in an animal model of DMD, Khurana sounds a cautionary
note for near-term clinical applications: “There are a number of
good reasons for parents not to start thinking of giving their children
heregulin at present; for one, we don't know anything about its potential
toxicity or side effects.” He stresses that this approach needs
to first be properly tested in controlled trials to measure its possible
long-term toxicity and efficacy in mdx mice, and then in additional animal-model
studies.

This work was funded in part by grants from Association Française
contre les Myopathies (France), Duchenne Parents Project (The Netherlands),
Lundbeckfonden (Denmark), as well as by the National Institutes of Health.
Other Penn researchers contributing to this study are Thomas O.B. Krag,
Sasha Bogdanovich, and M. Dominik Fischer, along with Elisabeth H. Javazon
and Alan W. Flake from the Children’s Hospital of Philadelphia and
Claus Juel, Jacob Hansen-Schwartz, and Lars Edvinsson from the Glostrup
Hospital & University of Copenhagen, Denmark.

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